Quinazoline ditosylate salt compounds

ABSTRACT

Ditosylate salts of 4-quinazolineamines are described as well as methods of using the same in the treatment of disorders characterized by aberrant erbB family PTK activity.

FIELD OF THE INVENTION

The present invention relates to quinazoline compounds, anhydrate andhydrate ditosylate salts thereof, as well as use and preparation of thesame. In particular, the invention relates to ditosylate salts of4-quinazolineamines. These compounds are inhibitors of various proteintyrosine kinases (PTKs) of the erbB family and consequently are usefulin the treatment of disorders mediated by aberrant activity of suchkinases.

PRIOR ART BACKGROUND OF THE INVENTION

PTKs catalyze the phosphorylation of specific tyrosyl residues invarious proteins involved in the regulation of cell growth anddifferentiation. (A. F. Wilks, Progress in Growth Factor Research, 1990,2, 97-111; S. A. Courtneidge, Dev. Supp.l, 1993, 57-64; J. A. Cooper,Semin. Cell Biol., 1994, 5(6), 377-387; R. F. Paulson, Semin. Immunol.,1995, 7(4), 267-277; A. C. Chan, Curr. Opin. Immunol., 1996, 8(3),394-401). Inappropriate or uncontrolled activation of many PTKs, i.e.aberrant PTK activity, for example by over-expression or mutation, hasbeen shown to result in uncontrolled cell growth.

Aberrant protein tyrosine kinase (PTK) activity has been implicated in avariety of disorders including psoriasis, rheumatoid arthritis,bronchitis, as well as cancer. Development of effective treatments forsuch disorders is a constant and ongoing enterprise in the medicalfield. The erbB family of PTKs, which includes c-erbB-2, EGFr, anderbB-4, is one group of PTKs that has attracted interest as atherapeutic target. Currently, of special interest, is the role of erbBfamily PTKs in hyperproliferative disorders, particularly humanmalignancies. Elevated EGFr activity has, for example, been implicatedin non-small cell lung, bladder, and head and neck cancers. Furthermore,increased c-erbB-2 activity has been implicated in breast, ovarian,gastric and pancreatic cancers. Consequently, inhibition of erbB familyPTKs should provide a treatment for disorders characterized by aberranterbB family PTK activity. The biological role of erbB family PTKs andtheir implication in various disease states is discussed, for instancein U.S. Pat. No. 5,773,476; International Patent Application WO99/35146; M. C. Hung et al, Seminars in Oncology, 26: 4, Suppl. 12(August) 1999, 51-59; Ullrich et al, Cell, 61: 203-212, Apr. 20, 1990;Modjtahedi et al, Int'l. J. of Oncology, 13: 335-342, 1998; and J. R.Woodburn, Pharmacol. Ther., 82: 2-3, 241-250, 1999.

International Patent Application PCT/EP99/00048 filed Jan. 8, 1999, andpublished as WO 99/35146 on Jul. 15, 1999, discusses PTKs including erbBfamily PTKs. This published application discloses bicyclicheteroaromatic compounds, includingN-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;(4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)quinazolin-4-yl)-amine; and(4-(3-Fluoro-benzyloxy)-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)quinazolin-4-yl)-amine as wellas hydrochloride salts thereof. These compounds show inhibition activityagainst erbB family PTKs. However, problems exist with the di-HCl saltin that it sorbs very large amounts of water at the humidities to whichit might be exposed (e.g., 20-75% relative humidity (RH)) if utilized ina medicament. As a result, suitability of the compound as a medicamentcould be compromised unless special handling and storage procedures wereinstituted.

The present inventors have now identified novel ditosylate salts of4-quinazolineamines, which are suitable as erbB family PTK inhibitors.These ditosylate salts have moisture sorption properties superior to thedi-HCl salts of 4-quinazoline amines disclosed in the art. Furthermore,the compounds may be prepared in crystal form and therefore haveenhanced physical stability. That is, the ditosylate salts of thepresent invention sorb much lower amounts of water when exposed to abroad range of humidities and can be prepared in a physically stablecrystal form, thus enhancing its suitability as a medicament.

DISCLOSURE OF THE INVENTION

In a first aspect of the present invention, there is provided a compoundof formula (I),

and anhydrate or hydrate forms thereof, wherein R₁ is Cl or Br; X is CH,N, or CF; and Het is thiazole or furan.

In a second aspect of the present invention, there is provided acompound of formula (II),

and anhydrate or hydrate forms thereof.

In a third aspect of the present invention, there is provided apharmaceutical composition including a therapeutically effective amountof a compound of formula (I) and anhydrate or hydrate forms thereof.

In a fourth aspect of the present invention, there is provided apharmaceutical composition including a therapeutically effective amountof a compound of formula (II) and anhydrate or hydrate forms thereof.

In a fifth aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being characterized byaberrant activity of at least one erbB family PTK, including:administering to said mammal a therapeutically effective amount of acompound of formula (I), or anhydrate or hydrate forms thereof.

In a sixth aspect of the present invention, there is provided a methodof treating a disorder mediated by aberrant protein tyrosine kinaseactivity in a mammal, including: administering to said mammal an amountof a compound of formula (I) or anhydrate or hydrate form thereof,effective to inhibit at least one erbB family protein.

In a seventh aspect of the present invention, there is provided acompound of formula (I), or anhydrate or hydrate forms thereof for usein therapy.

In an eight aspect of the present invention, there is provided use of acompound of formula (I), and anhydrate or hydrate forms thereof, in thepreparation of a medicament for use in the treatment of a disordercharacterized by aberrant erbB family PTK activity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the powder X-ray diffraction pattern ofN-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate anhydrate.

FIG. 2 depicts the powder X-ray diffraction pattern ofN-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate monohydrate.

FIGS. 3 (a) and (b) depict water sorption curves of (a)N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinaminemonohydrate ditosylate and (b) N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-[([2-(methanesulphonyl)ethyl]amino]methyl)-2-furyl]-4-quinazolinaminedi-HCl salt.

FIG. 4 depicts a comparison of the water sorption curves ofN-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinaminemonohydrate ditosylate and di-HCl salts.

FIG. 5 depicts the powder X-ray diffraction patterns forN-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineanhydrate and monohydrate crystal forms before and after stabilitytesting. The top panel shows the patterns for the pure crystal forms.The middle panel shows the initial and 1 day results for a slurry withwater activity equivalent to 7% RH. The bottom panel shows the initialand 1 day results for a slurry with water activity equivalent to 15% RH.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon having from one to twelve carbon atoms. Examples of “alkyl”as used herein include, but are not limited to, methyl, ethyl, ispropyl,n-propyl, n-butyl, n-pentyl, isobutyl, and the like.

It is to be understood that the following embodiments refer to compoundswithin the scope of formula (I) and formula (II), (III), or (IV) asdefined herein unless specifically limited by the definition of eachformula or specifically limited otherwise. It is also understood thatthe embodiments of the present invention, including uses, compositions,and processes for making, described herein, while being described withregard to compounds of formula (I) are applicable to compounds offormulae (II), (III), and (IV).

As recited above, the compounds of the present invention includecompounds of Formula (I) or anhydrate or hydrate forms thereof, where R₁is Cl or Br; X is CH, N, or CF; and Het is furan or thiazole.

The side chain CH₃SO₂CH₂CH₂NHCH₂ of the compounds of formula (I) may belinked to any suitable position of the group Het. Similarly, the phenylgroup of the quinazoline core may be linked to any suitable position ofthe group Het.

In one embodiment, R₁ is Cl, X is CH; and Het is furan; preferably acompound of Formula (II) and anhydrate or hydrate forms thereof.

The compound of formula (II) has the chemical nameN-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate.

In one embodiment, the compound is the monohydrate form of the compoundof formula II. In one embodiment, the monohydrate form has a watercontent of 1.5 to 3.0, preferably 1.7 to 2.5, more preferably 1.8 to 2.2percent by weight.

In another embodiment, the compound is the anhydrate form of thecompound of formula (II). In one embodiment, the anhydrate form has awater content of less than 1.5, preferably less than 1.0, morepreferably less than 0.5 percent by weight.

In a further embodiment, the compound is a compound of formula (II)characterized by a powder x-ray diffraction pattern including the peaksof Table I. TABLE I Two theta (deg)* d-spacing (angstroms) 4.8 18 8.7 1018.0 4.9 18.9 4.7 21.0 4.2 22.3 4.0*Based on Cu Kα radiation. Kα2 was removed prior to peak location

In another embodiment, the compound is a compound of formula (II)characterized by a powder x-ray diffraction pattern including the peaksof Table II. TABLE II Two theta (deg)* d-spacing (angstroms) 6.6 13 8.310 11.5 7.7 18.1 4.9 21.1 4.2*Based on Cu Kα radiation. Kα2 was removed prior to peak location

In an alternative embodiment, R₁ is Cl; X is CH; and Het is thiazole;preferably a compound of formula (III) and anhydrate or hydrate formsthereof.

The compound of formula III is(4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)quinazolin-4-yl)-amineditosylate.

In a further alternative embodiment, R₁ is Br; X is CH; and Het isfuran; preferably, a compound of formula (IV) and anhydrate or hydrateforms thereof.

The compound of formula (IV) is(4-(3-Fluoro-benzyloxy)-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)quinazolin-4-yl)-amineditosylate.

The compounds of formula (I), including the compounds of formulae (II),(III), and (IV), include within their scope substantially pure anhydrateor hydrate forms, as well as mixtures of hydrate and anhydrate forms. Itis also understood, that such compounds include crystalline or amorphousforms and mixtures of crystalline and amorphous forms.

While it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I), as well as anhydrate or hydrateforms thereof, may be administered as the raw chemical, it is possibleto present the active ingredient as a pharmaceutical composition.Accordingly, the invention further provides pharmaceutical compositions,which include therapeutically effective amounts of compounds of theformula (I) and anhydrate or hydrate forms thereof, and one or morepharmaceutically acceptable carriers, diluents, or excipients. Thecompounds of the formula (I) and anhydrate or hydrate forms thereof, areas described above. The carrier(s), diluent(s) or excipient(s) must beacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.According to another aspect of the invention there is also provided aprocess for the preparation of a pharmaceutical formulation includingadmixing a compound of the formula (I), or anhydrate or hydrate formsthereof, with one or more pharmaceutically acceptable carriers, diluentsor excipients.

Compounds of formula (I) and anhydrate or hydrate forms thereof may beformulated for administration by any route, and the appropriate routewill depend on the disease being treated as well as the subjects to betreated. Suitable pharmaceutical formulations include those for oral,rectal, nasal, topical (including buccal, sub-lingual, and transdermal),vaginal or parenteral (including intramuscular, sub-cutaneous,intravenous, and directly into the affected tissue) administration or ina form suitable for administration by inhalation or insufflation. Theformulations may, where appropriate, be conveniently presented indiscrete dosage units and may be prepared by any of the methods wellknow in the pharmacy art.

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of formula (I), and anhydrate or hydrate forms thereof,can also be administered in the form of liposome delivery systems, suchas small unilamellar vesicles, large unilamellar vesicles andmultilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of formula (I) and anhydrate and hydrate forms thereof mayalso be delivered by the use of monoclonal antibodies as individualcarriers to which the compound molecules are coupled. The compounds mayalso be coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e. by rapid inhalation, through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurised aerosols, nebulizers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

Also provided in the present invention, is a method for treating adisorder in a mammal characterized by aberrant activity of at least oneerbB family PTK which includes administering a therapeutically effectiveamount of a compound of formula (I), and anhydrate or hydrate formsthereof, to the mammal. The compounds of formula (I) and anhydrate orhydrate forms thereof are as described above.

The aberrant PTK activity referred to herein is any erbB family PTKactivity that deviates from the normal erbB family protein kinaseactivity expected in a particular mammalian subject. Aberrant erbBfamily PTK activity may take the form of, for instance, an abnormalincrease in activity, or an aberration in the timing and or control ofPTK activity. Such aberrant activity may result then, for example, fromoverexpression or mutation of the protein kinase leading toinappropriate or uncontrolled activation. Furthermore, it is alsounderstood that unwanted PTK activity may reside in an abnormal source,such as a malignancy. That is, the level of PTK activity does not haveto be abnormal to be considered aberrant, rather the activity derivesfrom an abnormal source.

The compounds of formula (I) and anhydrate or hydrate forms thereof, areinhibitors of one or more erbB family PTKs and as such have utility inthe treatment of disorders in mammals which are characterized byaberrant PTK activity, particularly humans. In one embodiment of thepresent invention, the disorder treated is characterized by at least oneerbB family PTK, selected from EGFr, c-erb-B2 and c-erb-B4, exhibitingaberrant activity. In another embodiment, the disorder treated ischaracterized by at least two erbB family PTKs, selected from EGFr,c-erb-B2 and c-erb-B4, exhibiting aberrant activity. In one embodimentof the treatment method, the compounds of formula (I) or anhydrate orhydrate forms thereof inhibit at least one erbB family PTK, selectedfrom EGFr, c-erb-B2 and c-erb-B4. In another embodiment of the treatmentmethod, the compounds of formula I or anhydrate or hydrate forms thereofinhibit at least two erbB family PTKs selected from EGFr, c-erb-B2 andc-erb-B4.

Accordingly, also provided is a method of treating a disorder mediatedby aberrant protein tyrosine kinase activity in a mammal, including:administering to said mammal an amount of a compound of formula (I) oranhydrate or hydrate form thereof, effective to inhibit at least oneerbB family protein. In one embodiment, the method includesadministering an amount of a compound of formula (I) or anhydrate orhydrate form thereof, effective to inhibit at least two erbB familyproteins.

The disorders referred to may be any disorder which is characterized byaberrant PTK activity. As recited above such disorders include, but arenot limited to, cancer and psoriasis. In a preferred embodiment, thedisorder is cancer. In a more preferred embodiment, the cancer isnon-small cell lung, bladder, prostate, brain, head and neck, breast,ovarian, gastric, colorectal, or pancreatic cancers.

A therapeutically effective amount of a compound of formula (I) andanhydrate or hydrate forms thereof will depend on a number of factorsincluding, but not limited to, the age and weight of the mammal, theprecise disorder requiring treatment and its severity, the nature of theformulation, and the route of administration, and will ultimately be atthe discretion of the attendant physician or veterinarian. Typically,the compounds of formula (I) and anhydrate or hydrate forms thereof willbe given for treatment in the range of 0.1 to 100 mg/kg body weight ofrecipient (mammal) per day and more usually in the range of 1 to 10mg/kg body weight per day. Acceptable daily dosages, may be from about0.1 to about 1000 mg/day, and preferably from about 0.1 to about 100mg/day.

The compounds of formula (I) and anhydrate or hydrate forms thereof,described above, are useful in therapy and in the preparation ofmedicaments for treating a disorder in a mammal, which is characterizedby aberrant activity of at least one erbB family PTK. In one embodimentof the present invention, the medicament prepared is useful in treatinga disorder characterized by at least one erbB family PTK, selected fromEGFr, c-erb-B2 and c-erb-B4, exhibiting aberrant activity. In anotherembodiment, the medicament prepared is useful in treating a disordercharacterized by at least two erbB family PTKs, selected from EGFr,c-erb-B2 and c-erb-B4, exhibiting aberrant activity. In one embodimentof the use, the compounds of formula (I) or anhydrate or hydrate formsthereof which are used to form the medicament, inhibit at least one erbBfamily PTK, selected from EGFr, c-erb-B2 and c-erb-B4. In anotherembodiment of the use, the compounds of formula (I) or anhydrate orhydrate forms thereof, which are used to form the medicament, inhibit atleast two erbB family PTKs selected from EGFr, c-erb-B2 and c-erb-B4,

The disorders treated are as described above.

The free base and HCl salts of the compounds of Formulae (I), (II),(III), and (IV), may be prepared according to the procedures ofInternational Patent Application No. PCT/EP99/00048, filed Jan. 8, 1999,and published as WO 99/35146 on Jul. 15, 1999, referred to above. Aschematic of such procedures is presented in Scheme A following. Thespecific page references given are to WO 99/35146. The free base of thecompound of formula II is used as an example of the general scheme.

The compound of formula (II), i.e., N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate has been prepared in two distinct forms, an anhydrate form(Formula II′ in Scheme B) and a monohydrate form (Formula II″ in SchemeB). The relationship of these forms is illustrated in Scheme B below.The anhydrate form of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate may be prepared by (a) reacting the tosylate salt of5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde(formula B in Scheme B) with 2-(methylsulfone)ethylamine intetrahydrofuran in the presence of diisopropyl-ethylamine followed by(b) the introduction of this solution into to a slurry of sodiumtriacetoxyborohydride in tetrahydrofuran at room temperature, (c) adding5N sodium hydroxide to adjust the pH to within a range of 10-11, (d)separating the organic tetrahydrofuran phase, and then (e) addingpara-toulenesulfonic acid hydrate to the organic phase to provide theditosylate anhydrate. Interconversion to the monohydrate and back to theanhydrate of the ditosylate salt compounds of the invention is asdepicted in Scheme B. The tosylate salt ofS-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehydeis prepared from the HCl salt of the carbaldehyde (Formula A of SchemeB). Preparation of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate and the anhydrate and monohydrate forms thereof are utilizedas an example. As recognized by those skilled in the art, othercompounds of formula I and anhydrate and hydrate forms thereof may beprepared by similar methods.

Compound A of Scheme B may be prepared by various synthetic strategies,other that the strategy recited in Scheme A above, utilizing thepalladium(0) mediated coupling of quinazoline and substituted furanintermediates.

Scheme C depicts five palladium(0) mediated coupling strategies, tosynthesize compound A of Scheme B. Synthesis (1), the prior art method,involves the use of commercially available 5-formyl-2-furylboronic acidin the Suzuki reaction. Synthesis (2) through (5) represent variousembodiments of the present invention which include: (2) generation of5-(diethoxymethyl)-2-furylboronic acid and its in situ use in the Suzukicoupling, (3) generation of 5-formyl-2-furylboronic acid from2-furaldehyde via in situ protection of the formyl moiety withN,O-dimethylhydroxylamine, and its in situ use in the Suzuki coupling,(4) generation of 5-formyl-2-furylboronic acid from5-bromo-2-furaldehyde via in situ protection of the formyl moiety withN,O-dimethylhydroxylamine, and its in situ use in the Suzuki coupling,and finally (5) the reverse Suzuki coupling of in situ generated4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}-6-quinazolinylboronic acid(prepared fromN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine)with 5-bromo-2-furaldehyde.

The reactions of Scheme C, are described following with reference toformulae (C), (A), and (B).

In (1) of Scheme C, the commercially available 5-formyl-2-furylboronicacid, i.e., the compound of formula (A) wherein R is —C(O)H and Z is—B(OH)₂, (Frontier Scientific, Inc.; Logan Utah), undergoes catalyticpalladium(0)-mediated coupling (Pure Appl. Chem. 1994, 66, 213; Synth.Commun. 1981, 11, 513) to form the desired compound of Formula (C) inhigh yields. Specifically, a compound of formula (C) is made by mixing acompound of formula (B), wherein L is iodine or bromine, preferablyiodine and U is an organic group as described herein, and 1.0-1.5 molarequivalents of 5-formyl-2-furylboronic acid, in an ethereal solvent suchas, but not limited to, diethyl ether, tetrahydrofuran, dioxane,ethylene gylcol diethyl ether also known as 1,2-diethoxyethane andethylene gylcol dimethyl ether also know as 1,2-dimethoxyethane or DME.A palladium catalyst is then added from a list that includespalladium(II) acetate, palladium(II) chloride, palladium on carbon,dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II),tetrakis(triphenylphosphine) pallladium(0),tris(dibenzylideneacetone)dipalladium(0), trans-dichlorobis(triphenylphosphine) palladium(II). The preferred catalyst is palladium on carbon.This reaction is then heated to between 25° C. and 120° C. for 1-24hours and then cooled to ambient temperature and filtered. The solutionis then treated with a mineral acid or an organic acid, such asp-toluenesulfonic acid monhydrate, and the compound of formula (C) isisolated in high yields as its mineral acid salt or p-toluenesulfonicacid salt.

Another approach to a compound of formula (C) employs advancing a crudesolution of a compound of formula (A) wherein Z is B(OH)₂ and R is—C(Q)(T)W where Q and T are O-alkyl, where alkyl is as defined hereinand is preferably ethyl, and W is hydrogen, in a palladium(0) mediatedbiaryl coupling (Suzuki cross coupling with in situ generated boronicacids is described in J. Org. Chem. 1996, 61, 9556, and references citedtherein) with a compound of formula (B), wherein L is iodine or bromineand U is an organic group, using “ligand-less” heterogeneous catalysiswith palladium on carbon. Such use of “ligand-less” palladium isreported in Org. Lett. 1999, 1, 965; Org. Process Res. Dev. 1999, 3,248; and Tetrahedron Lett. 1994, 35, 3277. A preferred embodiment ofthis approach, partially depicted in (2) of Scheme C, provides for (i)the in situ generation of furanyl lithiate, a compound of formula (A),wherein Z is Li and R is —C(Q)(T)W where Q and T are O-alkyl, preferablyethoxy, and W is hydrogen, (ii) subsequent generation of thecorresponding boronic acid, wherein Z is B(OH)₂ and R is —C(Q)(T)W whereQ and T are O-alkyl, preferably ethoxy, and W is hydrogen, and (iii) thepalladium(0)-mediated biaryl coupling to construct the desired compoundof formula (C). The process utilizes ethereal solvents. These etherealsolvents can include, but are not limited to, diethyl ether,tetrahydrofuran, dioxane, 1,2-diethoxyethane and DME. The preferredsolvent is DME. This preferred solvent was observed to offer significantimprovements over published procedures (Synth. Commun. 1998, 28, 1013)in the formation of 5-formyl-2-furylboronic acid synthesized from2-furaldehyde diethylacetal. Another suitable precursor to in situgenerated 5-formyl-2-furylboronic acid included2-(2-furyl)-1,3-dioxolane. Advantages of this process includedeprotonation of the compound of formula (A), wherein Z is hydrogen andR is —C(Q)(T)W where Q and T are O-alkyl, preferably ethoxy, and W ishydrogen, with alkyl lithiums, preferably n-butyl lithium, at highertemperatures (−20° C. in DME compared to −40° C. in tetrahydrofuran).Subsequent treatment of the compound of formula (A), wherein Z is Li andR is —C(Q)(T)W where Q and T are O-alkyl, preferably ethoxy, and W ishydrogen, with trialkyl borate, preferably triisopropyl borate in DMEalso provided higher conversion to the borate ester of the compound offormula (A), wherein Z is B(O-isopropyl)₃Li and R is —C(Q)(T)W where Qand T are O-alkyl, preferably ethoxy, and W is hydrogen. In preparationfor the subsequent Suzuki coupling, the in situ generated borate esterwas hydrolyzed to the boronic acid of the compound of formula (A),wherein Z is B(OH)₂ and R is —C(Q)(T)W where Q and T are O-alkyl, wherealkyl is as defined herein, preferably ethyl, and W is hydrogen by firsttreating with acetic acid followed by addition with water in thatspecific order at ambient temperature. It was also observed that thesuperior process improvements from the use of DME, as compared totetrahydrofuran, extended to the palladium(0)-mediated biaryl couplingwith boronic acid intermediate to give a compound of formula (C). Suchprocess improvements include more consistent yields, shorter reactiontimes, and enhanced purity profiles.

In another embodiment, compounds of formula (C) can be formed from apalladium(0) mediated biaryl union of 5-formyl-2-furylboronic acid, thecompound of formula (A) wherein Z is —B(OH)₂, generated in situ and acompound of formula (B), where L is iodine or bromine and U is anorganic group (See (3) of Scheme C). This process employs an in situprotection of the aldehyde functionality as an aminal lithiate, (Synlett1992, 615), as in the reaction of, for example, 2-furaldehyde with thelithium anion of a secondary amine chosen from morpholine,N,O-dimethylhydroxylamine, 1-methylpiperizine or N¹, N¹,N²-trimethyl-1,2-ethanediamine. The preferred amine in this process isN,O-dimethylhydroxylamine. Formation of the amine lithiate isaccomplished by treatment of the amine with an alkyl lithium reagent,preferably n-butyl lithium, in an ethereal solvent such astetrahydrofuran or DME at low temperature. The solution of the aminelithium anion is then mixed with 2-furaldehyde to form the in situaminal lithiate, a compound of formula (A), wherein Z is hydrogen, R is—C(Q)(T)W where Q is NR′R″, wherein R′ is O-alkyl, preferably methoxyand R″ is an alkyl as defined herein, preferably methyl or R′ and R″ areindependently alkyl as defined herein; T is O—Li and W is H. Thissolution is then treated with an additional molar equivalent of an alkyllithium, preferably n-butyl lithium, at low temperature to form thefuranyl lithate, a compound of formula (A), wherein Z is Li and R is—C(Q)(T)W where Q is NR′R″ where R′ is O-alkyl, preferably methoxy andR″ is alkyl, preferably methyl or R′ and R″ are independently alkyl asdefine herein, T is O—Li and W is H. This solution is then treated atlow temperature with a trialkylborate, preferably triisopylborate, toform a compound of formula (A), wherein Z is B(O-isopropyl)₃Li, R is—C(Q)(T)W where Q is NRR′, where R′ can be O-alkyl, preferably methoxyand R″ is an alkyl as defined herein, preferably methyl or R′ and R″ areindependently alkyl as defined herein; T is O—Li and W is hydrogen, andhydrolyzed to the 5-formyl-2-furylboronic acid in solution by theaddition of either a mineral or organic acid, such as acetic acid. Thisin situ generated 5-formyl-2-furylboronic acid readily undergoes apalladium(0)-mediated biaryl coupling to form a compound of formula (C).

The process, described in the preceding paragraph, to obtain a compoundof formula (C), can also be employed when using a halogen (Z is bromineor iodine) substituted 2-furaldehyde derivatives, preferably5-bromo-2-formylfuran. That is, a compound of formula (A) where Z isbromine and R is —C(O)H (See (4) of Scheme C).

Alternatively, another synthetic strategy to compounds of formula (C)can be constructed from a palladium(0) mediated biaryl coupling ofN-heteroaryl boronic acids, such as a compound of formula (B), wherein Lis B(OH)₂ and U is an organic group, with 5-halogen-2-formylfuranderivatives, that is a compound of formula (A) where Z is bromine oriodine and R is —C(O)H. (See (5) of Scheme C). A process for making aN-heteroaryl boronic acid intermediate of formula (B) involves thetreatment of a compound of formula (B), wherein L is iodine and U is anorganic group, with an alkylmagnesium halide reagent, preferablyethylmagnesium bromide. The reaction is performed in an ethereal solventsuch as tetrahydrofuran or DME at low temperature. This mixture is thentreated with a trialkylborate, preferably triisopropyl borate followedby slow addition of an alkyllithium, preferably n-butyllithium, whilemaintaining the reaction at low temperature. This is then followed bythe addition of a mineral acid or organic acid, preferably acetic acid.This gives an N-heteroaryl boronic acid intermediate of formula (B),wherein L is B(OH)₂ and U is an organic group in solution. To this isthen added 5-halogen-2-furaldehyde- (halogen is bromine or iodine),preferably 5-bromo-2-furaldehyde, a co-solvent such asN,N-dimethylacetamide, an aqueous base, such as sodium carbonate and apalladium catalyst, such asdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct. This solution is then heated to a sufficienttemperature to provide conversion to the desired compound of formula(C).

A different synthetic strategy for the construction of a compound offormula (C), is to use a Heck-type reaction (Bull. Chem. Soc. Jpn. 1973,46, 1220; Heterocycles 1990, 31, 1951; Synthesis 1984, 488; J. Org.Chem. 1985, 50, 5272) to couple 2-furaldehyde, a compound of formula (A)wherein Z is hydrogen and R is —C(O)H, in a regioselective manner withan intermediate of formula B, wherein L is iodine or bromine and U is anorganic group. The regioselective palladium catalyzed arylation of2-furaldehyde, in the 5-position is unprecedented in the chemicalliterature. Other suitable substitutes for 2-furaldehyde in this processinclude 2-furaldehyde diethylacetal, 2-(2-furyl)-1,3-dioxolane,2-furanoic acid and esters of 2-furanoic acid such as methyl 2-furanoateor ethyl 2-furanoate. The process for the synthesis of a compound offormula (C) employing this strategy entails mixing an appropriatesolvent, such as N,N-dimethylformamide, N-methylpyrrolidinone, toluene,dimethylacetamide, water, acetonitrile or mixtures thereof, preferablyN,N-dimethylformamide, with an organic amine base, such as triethylamineand diisopropylethylamine or an alkali metal carboxylate base, such assodium carbonate, potassium carbonate, cesium carbonate, calciumcarbonate, sodium acetate and potassium acetate, preferably potassiumacetate, and 2-furaldehyde. This is then followed by the addition of atrialkyl- or triarylphosphine, such as tri-o-tolylphosphine,triphenylphosphine, tri-tert-butylphosphine, tri-2-furylphosphine,tricyclohexylphosphine, preferably tricyclohexylphosphine. A palladiumcatalyst is added from a list that includes, but is not limited to,palladium(II) acetate, palladium(II) chloride, palladium on carbon,dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II),tetrakis(triphenylphosphine) paliladium(0),tris(dibenzylideneacetone)dipalladium(0). trans-dichlorobis(triphenylphosphine)palladium(II), preferably palladium(II) chloride.This mixture is then heated and a solution of a compound of formula (B),wherein L is iodine or bromine, preferably iodine, is slowly added. Thisreaction mixture is then heated for 10-20 hours at which point thereaction mixture is cooled to ambient temperature and filtered. Additionof a mineral acid or organic acid, such as p-toluenesulfonic acid,provides an isolated compound of formula (C) as its salt.

In one embodiment of the present invention, there is provided a processfor preparing a compound of formula (C),

including the steps of:

reacting a compound of formula (A)

with a compound of formula (B)

to form the compound of formula (C),wherein U is an organic group; andthe compound of formula (A) is generated in situ, and

L is iodine or bromine;

R is —C(Q)(T)W where Q and T are independently selected from —OCH₃, or

—OCH₂CH₃ and W is hydrogen; and

Z is B(OH)₂; or the compound of formula (A) is generated in situ, and

L is iodine or bromine;

R is —C(O)H, and

Z is B(OH)₂; or

the compound of formula (B) is generated in situ, and

L is B(OH)₂;

R is —C(O)H; and

Z is bromine; or

the compound of formula (B) is reacted with the compound of formula (A)regioselectively, where neither of the compounds of formula (A) or (B)is generated in situ, and

L is iodine or bromine;

R is —C(O)H; and

Z is hydrogen.

As indicated above U may be any suitable organic group. In oneembodiment, U represents a phenyl, pyridyl, 3H-imidazolyl, indolyl,isoindolyl, indolinyl, isoindolinyl, 1H-indazolyl,2,3-dihydro-1H-indazolyl, 1H-benzimidazolyl,2,3-dihydro-1H-benzimidazolyl or 1H-benzotriazolyl group, substituted byan R² group and optionally substituted by at least one independentlyselected R⁴ group.

R² is selected from a group comprising benzyl, halo-, dihalo- andtrihalobenzyl, benzoyl, pyridylmethyl, pyridylmethoxy, phenoxy,benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl;

or R² represents trihalomethylbenzyl or trihalomethylbenzyloxy;

or R² represents a group of formula

wherein each R³ is independently selected from halogen, C₁₋₄ alkyl andC₁₋₄ alkoxy; and n is 0 to 3.

In a preferred embodiment U represents a phenyl, indolyl, or1H-indazolyl group substituted by an R group and optionally substitutedby at least one independently selected R⁴ group.

In a more preferred embodiment U represents a phenyl or 1H-indazolylgroup substituted by an R² group and optionally substituted by at leastone independently selected R⁴ group.

R⁴ is selected from the group hydroxy, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, di[C₁₋₄ alkyl]amino,C₁₋₄ alkylthio, C₁₋₄ alkylsulphinyl, C₁₋₄ alkylsulphonyl, C₁₋₄alkylcarbonyl, carboxy, carbamoyl, C₁₋₄ alkoxycarbonyl, C₁₋₄alkanoylamino, N—(C₁₋₄ alkyl)carbamoyl, N,N-di(C₁₋₄ alkyl)carbamoyl,cyano, nitro and trifluoromethyl.

In a more preferred embodiment, where U represents a phenyl group thegroup R² is in the para-position relative to the bond from U to thelinking NH group.

In a further more preferred embodiment, where U represents a1H-indazolyl group the group R² is in the 1-position of the indazolylgroup.

In a preferred embodiment R² represents benzyl, pyridylmethyl, phenoxy,benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl.

In a further preferred embodiment R² represents trihalomethylbenzyloxy.

In a further preferred embodiment R² represents a group of formula

-   -   wherein Hal is Br or Cl, particularly Cl, more especially        wherein the Hal substituent is in the position marked with a        star in the ring as shown.

In a more preferred embodiment R² represents benzyloxy, fluorobenzyloxy(especially 3-fluorobenzyloxy), benzyl, phenoxy and benzenesulphonyl.

In a further more preferred embodiment R² represents bromobenzyloxy(especially 3-bromobenzyloxy) and trifluoromethylbenzyloxy.

In a further preferred embodiment, the ring U is not substituted by anR⁴ group; in an especially preferred embodiment U is phenyl or indazolylunsubstituted by an R⁴ group.

In a further preferred embodiment the ring U is substituted by an R⁴group selected from halo or C₁₋₄ alkoxy; especially chloro, fluoro ormethoxy.

In a more preferred embodiment the ring U is substituted by an R⁴ groupwherein R⁴ represents halo, especially 3-fluoro.

In an especially preferred embodiment U together with R⁴ representsmethoxyphenyl, fluorophenyl, trifluoromethylphenyl or chlorophenyl.

In a more especially preferred embodiment U together with R⁴ representsmethoxyphenyl or fluorophenyl.

In an especially preferred embodiment the group U together with thesubstituent(s) R² and R⁴ represents benzyloxyphenyl,(fluorobenzyloxy)phenyl, (benzenesulphonyl)phenyl, benzylindazolyl orphenoxyphenyl.

In a more especially preferred embodiment the group U together with thesubstituent(s) R² and R⁴ represents benzyloxyphenyl,(3-fluorobenzyloxy)phenyl, (benzenesulphonyl)phenyl or benzylindazolyl.

In another more especially preferred embodiment the group U togetherwith the substituent(s) R² and R⁴ represents (3-bromobenzyloxy)phenyl,(3-trifluoromethylbenzyloxy)phenyl, or(3-fluorobenzyloxy)-3-methoxyphenyl.

In another more especially preferred embodiment the group U togetherwith the substituent(s) R² and R represents3-fluorobenzyloxy-3-chlorophenyl, benzyloxy-3-chlorophenyl,benzyloxy-3-trifluoromethylphenyl, (benzyloxy)-3-fluorophenyl,(3-fluorobenzyloxy)-3-fluorophenyl or (3-fluorobenzyl)indazolyl.

In a most especially preferred embodiment the group U together with thesubstituent(s) R² and R⁴ represents benzyloxyphenyl or(3-fluorobenzyloxy)phenyl.

Halo is, for example, fluoro, chloro, bromo or iodo; preferably it isfluoro, chloro or bromo, more preferably fluoro or chloro.

C₁₋₄ alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl or tert-butyl; preferably it is methyl, ethyl,propyl, isopropyl or butyl, more preferably methyl.

C₂₋₄ alkenyl is, for example, ethenyl, prop-1-enyl or prop-2-enyl;preferably it is ethenyl.

C₂₋₄ alkynyl is, for example, ethynyl, prop-1-ynyl or prop-2-ynyl;preferably it is ethynyl.

C₁₋₄ alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; preferably it ismethoxy, ethoxy, propoxy, isopropoxy or butoxy; more preferably it ismethoxy.

C₁₋₄ alkylamino is, for example, methylamino, ethylamino or propylamino;preferably it is methylamino.

di[C₁₋₄ alkyl]amino is, for example, dimethylamino, diethylamino,N-methyl-N-ethylamino or dipropylamino; preferably it is dimethylamino.

C₁₋₄ alkylthio is, for example, methylthio, ethylthio, propylthio orisopropylthio, preferably methylthio.

C₁₋₄ alkylsulphinyl is, for example, methylsulphinyl, ethylsulphinyl,propylsulphinyl or isopropylsulphinyl, preferably methylsulphinyl.

C₁₋₄ alkylsulphonyl is, for example, methanesulphonyl, ethylsulphonyl,propylsulphonyl or isopropylsulphonyl, preferably methanesulphonyl.

C₁₋₄ alkylcarbonyl is, for example methylcarbonyl, ethylcarbonyl orpropylcarbonyl.

C₁₋₄ alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl or tert-butoxycarbonyl.

C₁₋₄ alkanoylamino (where the number of carbon atoms includes the COfunctionality) is, for example, formamido, acetamido, propionamido orbutyramido.

N-(C₁₋₄ alkyl)carbamoyl is, for example, N-methylcarbamoyl orN-ethylcarbamoyl.

N,N-di(C₁₋₄ alkyl)carbamoyl is, for example, N,N-dimethylcarbamoyl,N-methyl-N-ethylcarbamoyl or N,N-diethylcarbamoyl.

The following examples are intended for illustration only and are notintended to limit the scope of the invention in any way. The physicaldata given for the compounds exemplified is consistent with the assignedstructure of those compounds.

EXAMPLES

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

g (grams); mg (milligrams);

L (liters); mL (milliliters);

μL (microliters); psi (pounds per square inch);

M (molar); mM (millimolar);

N (Normal) Kg (kilogram)

i. v. (intravenous); Hz (Hertz);

MHz (megahertz); mol (moles);

mmol (millimoles); RT (room temperature);

min (minutes); h (hours);

mp (melting point); TLC (thin layer chromatography);

T_(r) (retention time); RP (reverse phase);

THF (tetrahydrofuran); DMSO (dimethylsulfoxide);

EtOAc (ethyl acetate); DME (1,2-dimethoxyethane);

-   -   DCM (dichloromethane); DCE (dichloroethane);    -   DMF (N,N-dimethylformamide); HOAc (acetic acid);

TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl);

TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl);

HPLC (high pressure liquid chromatography);

Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade). All reactions conducted under an inert atmosphereat room temperature unless otherwise noted.

¹H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, aVarian Unity-400 instrument, or a General Electric QE-300. Chemicalshifts are expressed in parts per million (ppm, δ units). Couplingconstants are in units of hertz (Hz). Splitting patterns describeapparent multiplicities and are designated as s (singlet), d (doublet),t (triplet), q (quartet), m (multiplet), br (broad).

Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA,JOEL SX-102, or a SCIEX-APliii spectrometer; high resolution MS wereobtained using a JOEL SX-102A spectrometer. All mass spectra were takenunder electrospray ionization (ESI), chemical ionization (CI), electronimpact (EI) or by fast atom bombardment (FAB) methods. Infrared (IR)spectra were obtained on a Nicolet 510 FT-IR spectrometer using a 1-mmNaCl cell. All reactions were monitored by thin-layer chromatography on0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light,5% ethanolic phosphomolybdic acid or p-anisaldehyde solution. Flashcolumn chromatography was performed on silica gel (230-400 mesh, Merck).Optical rotations were obtained using a Perkin Elmer Model 241Polarimeter. Melting points were determined using a MeI-Temp IIapparatus and are uncorrected.

Example 1 Preparation of5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde

To a reaction vessel was addedN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine (100mg; 0.198 mmol), 2-formylfuran-5-boronic acid (Frontier Scientific, 42mg; 0.297 mmol), 10% palladium on activated carbon (5 mg; 0.05 wt), DME(2.0 mL), MeOH (1.0 mL) and triethylamine (83 μL). After heating at 50°C. for 14 h, a HPLC indicated 98.5% clean conversion. ¹H NMR (d₆-DMSO)δ: 11.44 (s, 1H), 9.38 (s, 2H), 9.11 (s, 1H), 8.90 (s, 1H), 8.39 (dd,1H, J=8 and 4 Hz), 7.89 (d, 1H, J=12 Hz), 7.84 (d, 1H, J=4 Hz), 7.60(dd, 1H, J=8 and 4 Hz), 7.47-7.42 (m, 2H), 7.44 (M′BB′, 2H, J_(AB)=8Hz), 7.35-7.25 (m, 3H), 7.24 (d, 1H, J=4 Hz), 7.16 (dt, 1H, J=8 and 4Hz), 7.06 (AA′BB′, 2H, J_(AB)=8 Hz, 6.84 (d, 1H, J=4 Hz), 5.27 (s, 2H),4.43 (s, 2H), 3.61-3.50 (m, 2H), 3.47-3.36 (m, 2H), 3.09 (s, 3H), 2.23(s, 6H).

Example 2 Preparation of5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde

(i) In situ Preparation of 2-diethylacetal-furan-5-boronic acid

A 20 L reaction vessel was charged with 6.7 volumes of DME and 0.67 wt.,(740 grams, 410 mL, 4.35 mol) of 2-furaldehyde diethyl acetal and cooledto −40° C. under reaction/contents control. n-Butyllithium, 1.32 wt.(2.5 M in hexanes, 1.45 kg, 5.22 mole) was added over ca. 40 minutesusing a ChemTech CP120 metering pump containing a ceramic head. Theinternal temperature rose to −31° C. The reaction mixture turned verydark, but was homogeneous. After the addition was complete, the lineswere flushed with ca. 0.17 volumes of hexane directly into the reactionvessel. When the internal temperature decreased to −40° C., the reactionmixture was stirred for an additional 2.5 hrs. After 2.5 hours, 1.1 vol(0.89 wt, 982 grams, 5.22 mol) of triisopropylborate was added via themetering pump over 20 minutes. A slight exotherm was observed during thefirst half of the addition, which peaked at about −31° C. An additional0.15 vol of hexane was used to flush the pump lines into the reactiontank. After 2 hours, (with 30 minutes at −40° C.), the temperature ofthe reaction was ramped up to 25° C. over 60 minutes. When the internaltemperature reached 25° C., a 1 mL aliquot was removed for an in-processcheck. [Sample preparation: Two drops of the reaction mixture werediluted with 1 mL of CH₃CN and 100 mL of 1N HCl and subjected to LC at280 nM.] The boronic acid/2-furfural ratio was 119:1. At this point,0.29 vol of acetic acid was added and the reaction mixture was stirredfor 30 minutes. Water, 0.36 vol, was added after 30 min. This reactionmixture was used directly in the next step.

(ii) Preparation of5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde4-methylbenzenesulfonate using in situ prepared2-diethylacetal-5-boronic acid

To the reaction mixture from above was added 3.4 vol (3.7 L) of ethanolover a 5 minute period via vacuum addition. Triethylamine, 0.69 vol (760mL, 5.45 mol) was added followed by 1 wt (1100 g, 2.18 mol) ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine and3 wt % of 10% Pd/C [Palladium, 10 wt % (dry basis) on Activated Carbon,50% Water Wet, Degussa Type E101NEIW]. The reactor, in reactor controlmode, was set to 62° C. The internal temperature was observed to rise to58° C. over ca. 2 hrs. After ca. 14 hours, an aliquot was removed for anin-process check. [Sample preparation: 15 μL was diluted with 1 mL ofMeOH and 250 μL of 1 N HCl and subjected to Fast LC at 220 nM.] At thistime, the reactor was cooled to 25° C. The dark reaction mixture wastransferred to the second reactor through a teflon-lined stainless steeljacketed transfer hose outfitted with an in-line 5.0 μm cartridge filter(Pall part no. R1f/050, lot no. FJ0807) and an in-line 0.45 μm filter(Meisner CLMF 0.4-662, lot no. 4087-R-#F). The first reactor was rinsedwith 0.5 vol of DME and was passed through the transfer hose so as towash the solids through the filter cartridges. p-Toluenesulfonic acidmonohydrate, 1.55 wt (1700 g, 8.72 mol) was dissolved in 2.27 vol ofdeionized water and the solution was added to the reaction mixture over5 minutes. After stirring at 25° C. for 1 hour, the product wascollected in a ceramic filter lined with medium filter paper. Thereactor and filter cake were rinsed with 0.9 vol of a 1:1 DME/watersolution. After suctioning dry for 4 hours, the yellow filter cake wastransferred to two glass trays and placed in the drying oven (50-55° C.)under house vacuum (18 in Hg) with a nitrogen bleed. The two glass trayswere removed from the oven and allowed to cool to room temperature andsampled accordingly. The isolated yield of the title compound was 1230grams (1.12 wt., 87% th; 1410 g Th) which existed as a yellowish solid.¹H NMR (d₆-DMSO) δ: 11.44 (s, 1H), 9.38 (s, 2H), 9.11 (s, 1H), 8.90 (s,1H), 8.39 (dd, 1H, J=8 and 4 Hz), 7.89 (d, 1H, J=12 Hz), 7.84 (d, 1H,J=4 Hz), 7.60 (dd, 1H, J=8 and 4 Hz), 7.47-7.42 (m, 2H), 7.44 (AA′BB′,2H, J_(AB)=8 Hz), 7.35-7.25 (m, 3H), 7.24 (d, 1H, J=4 Hz), 7.16 (dt, 1H,J=8 and 4 Hz), 7.06 (AA′BB′, 2H, J_(AB)=8 Hz, 6.84 (d, 1H, J=4 Hz), 5.27(s, 2H), 4.43 (s, 2H), 3.61-3.50 (m, 2H), 3.47-3.36 (m, 2H), 3.09 (s,3H), 2.23 (s, 6H).

Example 3 Preparation of5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehydeusing in situ protected 2-furaldehyde

N,O-dimethylhydroxylamine hydrochloride (629 mg; 6.32 mmol) wassuspended in THF (19 mL; 40 Vol), and the flask was cooled to −40° C.(Cryocool-controlled isopropanol bath). n-Butyllithium (2.5 M solutionin hexanes; 5.3 mL; 13.2 mmol) was added at a dropwise rate while theinternal temperature rose to −12° C. However, the mixture quickly cooledback to −40° C. After 30 min at −40° C., 2-furaldehyde (481 μL; 5.74mmol) was rapidly added to the mixture which caused the internaltemperature to rise to −28° C. Again, the temperature dropped quicklyback to −40° C. After 15 min at −40° C., n-butyllithium (2.5 M solutionin hexanes; 2.8 mL; 6.89 mmol) was added at a dropwise rate, while theinternal temperature was maintained below −35° C. During the course ofaddition, the mixture turned yellow. After the addition was complete,the mixture was allowed to stir at 40° C. for 1 h. Triisopropylborate(2.0 mL; 8.62 mmol) was added at a dropwise rate, while the internaltemperature was maintained below −35° C. After the addition wascomplete, the cooling was turned off. A HPLC indicated 83.7% of desiredboronic acid, 6.2% of starting material. When the internal temperaturereached-20° C., the mixture was quenched by addition of acetic acid (462μL; 8.04 mmol) and allowed to warm to ambient temperature. The materialwas advanced without purification or isolation directly to the SuzukiCoupling reaction.

To the reaction vessel containing crude boronic acid was addedN,N-dimethylacetamide (13 mL), 1.16 M aqueous Na₂CO₃ solution (7.3 mL;7.38 mmol),N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine(1.87 g; 3.69 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (15 mg; 0.0185 mmol). Upon addition of the base,the internal temperature rose to ca. 28° C. The reaction mixture washeated to 50° C. (internal temperature) with an oil bath. The reactionmixture was filtered through a compressed pad of Celite and the solidswere washed with THF. The isolated solution was then diluted with ethylacetate and aqueous hydrochloric acid was added. The layers wereseparated and the aqueous was neutralized and diluted with ethylacetate. The layers were separated and the organic layer was dried oversodium sulfate, filtered and concentrated under vacuum to give the titlecompound. LC retention time of title compound: 4.9 minutes.

Example 4 Preparation of5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehydehydrochloride using in situ protected 5-bromo-2-furaldehyde

N,O-dimethylhydroxylamine hydrochloride (3.04 g; 30.49 mmol) wassuspended in THF (40 mL), and the flask was cooled to −78° C. (dryice—acetone bath). n-Butyllithium (2.5 M solution in hexanes; 24.4 mL;60.98 mmol) was added dropwise to this cold suspension, which becamehomogeneous. The acetone/CO₂ bath was replaced by a water/ice bath (0°C.), and the mixture turned pale yellow. After stirring for 15 min at 0°C., the solution was cooled back to −78° C., and 5-bromo-2-furaldehyde(5.00 g dissolved in 10 mL of THF; 27.72 mmol) was added at a dropwiserate. Fifteen minutes after the addition had been completed, thereaction mixture was allowed to warm to 0° C. in a water/ice bath, and15 minutes later, it was cooled back to −78° C. ten minutes later,triisopropylborate (18.8 mL; 83.16 mmol) was added to the cold mixturein one portion, followed by dropwise addition of n-butyllithium (2.5 Msolution in hexanes; 27.7 mL; 69.30 mmol). After 30 min at −78° C.,acetic acid (6.5 mL; 102.6 mmol) was added to the cold reaction mixture,which was then allowed to warm to ambient temperature. The material wasadvanced without purification or isolation directly to the SuzukiCoupling reaction.

To the reaction vessel containing crude boronic acid was addedN,N-dimethylacetamide (54 mL), water (11 mL),N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine(10.78 g; 21.32 mmol), solid Na₂CO₃ (6.85 g; 63.97 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (174 mg; 0.21 mmol) to yield an orange reactionmixture. The reaction mixture was heated to 80° C., and no color changewas noted. After 28.5 h total reaction time, the reaction mixture wasallowed to cool to ambient temperature. The mixture was diluted with THF(54 mL), treated with 100 mesh Darco® G-60 Activated Carbon (696 mg),Hyflo Super Cel® (348 mg) and stirred at ambient temperature for >2h.The precipitates were removed by suction filtration through frittedfunnel loaded with Hyflo Super Cel® and washed with THF (5×22 mL) untilthe THF solvent displayed no more color. The filtrate was treated withconcentrated aqueous HCl (7.1 mL; 85.3 mmol) and water (80 mL) andallowed to stir at ambient temperature for 2 h. The precipitate wasfiltered through a fritted funnel and rinsed with 33% isopropanol/water(54 mL), water (54 mL) and 33% isopropanol/water (54 mL), and thenallowed to air-dry for 2 h. The yellowish brown solid was transferredinto a vacuum desiccator and allowed to dry in vacuo overnight. Thereaction gave 9.01 g of the title compound (83% yield) as a beige-brownpowder. LC retention time of title compound: 4.9 minutes.

Example 5 Preparation of5-(4-[3-chloro-4-(3-fluorobenzyloxy)-aniliino]-6-quinazolinyl)-furan-2-carbaldehydeusing in situ generated4-(3-chloro-4-[(3-fluorobenzyl)oxyjanilino]-6-quinazolinylboronic acid

N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine (200mg; 0.395 mmol) was dissolved in THF (2.0 mL), giving a yellowishsolution. The mixture was cooled to 0° C. (water/ice bath) and thentreated with ethylmagnesium bromide (1.0 M solution in THF; 475 μL;0.475 mmol) to yield a homogeneous bright yellow solution, which wascooled, to −78° C. Triisopropylborate (373 μL; 1.582 mmol) was addedrapidly, followed by slow addition of n-butyllithium (2.5 M solution inhexanes; 395 μL; 0.989 mmol). When the reaction completed as verified byHPLC, acetic acid (84 μL; 1.463 mmol) was added to quench the reaction.To the crude yellow slurry of boronic acid in THF was added5-bromo-2-furaldehyde (107 mg; 0.593 mmol), followed byN,N-dimethylacetamide (2.0 mL), which caused the mixture to becomehomogeneous, 1.016 N aqueous Na₂CO₃ (1.2 mL; 1.185 mmol) and finallydichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (16 mg; 0.020 mmol). The mixture was heated at80° C. A HPLC check after 15 h indicated 95% clean conversion to thetitle compound. LC retention time: t=4.9 min.

Example 6 Regioselective preparation of5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde4-methylbenzenesulfonate

A mixture of 2-furaldehyde (5.7 mL, 69 mmol), potassium acetate (1.4 g,14 mmol), and palladium(II) chloride (61 mg, 0.35 mmol) in 35 mL of DMFwas degassed for 10 minutes by vigorously bubbling N₂ through themixture while stirring. The catalyst mixture was subsequently warmed to110° C. A solution ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine (3.5g, 6.9 mmol) in 55 mL of DMF was degassed in a similar manner and thenadded to the catalyst mixture via syringe pump over 10 hours. After theaddition was complete, the reaction temperature was maintained at 110°C. for an additional two hours. After cooling to room temperature, themixture was poured into 125 mL of water. The precipitate was collectedon coarse filter paper and washed with water (ca. 7 mL). The solid wasre-dissolved in warm (50° C.) DME. To this solution was added (2.0 g;10.4 mmol) of p-toluenesuflonic acid monohydrate. The temperature waslowered to 35° C. and the mixture was stirred at this temperatureovernight. Water (60 mL) was added to induce further precipitation. Theproduct was collected on coarse filter paper and subsequently washedwith 30-40 mL of DME/water (1:1). The filter cake was dried at 50° C.under house vacuum overnight to provide 2.5 g (55%) of the titlecompound. ¹H NMR (d₆-DMSO) δ: 11.44 (s, 1H), 9.38 (s, 2H), 9.11 (s, 1H),8.90 (s, 1H), 8.39 (dd, 1H, J=8 and 4 Hz), 7.89 (d, 1H, J=12 Hz), 7.84(d, 1H, J=4 Hz), 7.60 (dd, 1H, J=8 and 4 Hz), 7.47-7.42 (m, 2H), 7.44(AA′BB′, 2H, J_(AB)=8 Hz), 7.35-7.25 (m, 3H), 7.24 (d, 1H, J=4 Hz), 7.16(dt, 1H, J=8 and 4 Hz), 7.06 (AA′BB′, 2H, J_(AB)=8 Hz, 6.84 (d, 1H, J=4Hz), 5.27 (s, 2H), 4.43 (s, 2H), 3.61-3.50 (m, 2H), 3.47-3.36 (m, 2H),3.09 (s, 3H), 2.23 (s, 6H).

Example 7 Preparation of5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde4-methylbenzenesulfonate

A 2 liter, 3 neck round bottom flask equipped with a mechanical stirrerwas charged with 74.95 grams of the HCl salt of5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde(prepared according to Procedure C, page 56 of WO 99/35146: See SchemeA, Procedure C above) and 749.5 mL THF. To this slurry was charged 84.45mL of 2M NaOH and the reactants were stirred for 30 minutes. The layerswere separated and then the organic layer was washed with 160 mL of H₂O.The organic layer was slurried with 3.75 grams of Darco G60 and filteredthrough celite. The filtrate was collected and slowly added to 33.54grams of toluenesulfonic acid monohydrate with rapid stirring. Thesolids slowly precipitated out at ambient temperature. The mixture wascooled to 0° C. and stirred for 10 min. The mixture was filtered andpulled dry with a rubber dam, then dried in vacuo at 50° C. overnight.The yield of5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde4-methylbenzene sulfonate was 84.25 grams (88.8%).

Example 8 Preparation of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino)methyl)-2-furyl]-4-quinazolinamineditosylate anhydrate (anhydrate form of compound of formula II)

To a 20 L reactor was added 13.3 vol of THF followed by 0.62 wt (2.93mol) of NaBH(OAc)₃. The 20 L reactor was set to maintain contents at 20°C. A second 20 L reactor was charged with 1000 grams, (1.55 mol) of5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde4-methyl benzenesulfonate prepared by the procedure of Example 7 and 6.7vol of THF. To the THF solution of5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde4-methylbenzenesulfonate was added 0.325 vol (1.86 mol)diisopropylethylamine followed by 0.32 wt of2-(methylsulfone)ethylamine, (321 g, 2.6 mol) and 0.15 vol of IPA. After1 hour, the preformed imine/THF solution was transferred by vacuum tothe stirred suspension of NaBH(OAc)₃ in the first 20 L reactor over 10minutes. After 90 minutes, 4 vol of 5N NaOH was added over 40 min via apump. This solution was allowed to stir for 15 minutes after which thestirrer was switched off and the layers were allowed to separate. Theaqueous layer was drained from the bottom of the reactor and the organiclayer transferred to the empty 20 L reactor through a teflon-linedstainless steel jacketed transfer hose outfitted with an in-line 0.45 μmfilter. To this solution was added a 2 vol THF solution of 4 wt (1180 g,6.2 mole) of p-toluenesulfonic acid monohydrate over 5 min. A yellowishprecipitate was observed to come out of solution and this was allowed tostir at room temperature for 12 hours. The reaction was drained from thebottom of the reactor and filtered through a ceramic filter lined withpaper. The yellow filter cake was washed with 1 vol of a 95:5 THF/watersolution and allowed to air dry overnight. After suctioning dry for 12hours, the yellow filter cake was transferred to two glass trays andplaced in the drying oven (42° C.) under house vacuum (18 in Hg) with anitrogen bleed. The two glass trays were removed from the oven andallowed to cool to room temperature and sampled accordingly. Theisolated yield of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methane-sulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate (anhydrate) was 1264 grams (1.3 wt, 88%; 1443 g Th) and was ayellow solid.

Approximately 50 mg of the product was transferred to a Karl FisherVolumetric Moisture Apparatus (model DL35, Mettler, Hightstown, N.J.),which was operated according to the manufacturer's instructions. Theanhydrate water content was determined to be 0.31%.

Example 9 X-Ray Diffraction of Anhydrate Ditosylate Salt

An anhydrate ditosylate salt sample prepared according to Example 8 wasdusted on to a silicon zero background plate of a Scintag XDS2000Diffractometer. The powder x-ray diffraction pattern of the sample wasobtained under the following conditions. Geometry: θ/θ Asset: 0038018Seifert High Voltage ID3000 generator, S/N 90 67 1422 X-ray tube tower:Seifert type V4, 60 kV max, 40 mA max, X-ray diffraction tube: AEGFK-60-10 copper anode tube, 60 kV max, 2 kW max, normal focus (1 × 10mm) Scintag Peltier cooled Si(Li) Solid 250 mm State Detector Model B3A,Goniometer radius: Operating Conditions: X-ray tube voltage: 45 kV X-raytube current: 40 mA Scan Conditions: chopper: 0.02 deg continuous scanmode 0.1 deg 2θ/min scan rate: sample spinner: ON (1 rotation/sec) DS =1 mm; SS(i) = 2 mm SS(d) = 0.5 mm; RS = 0.3 mm DS = divergent slit(incident beam) SS(i) = scatter slit (incident) SS(d) = scatter slit(diffracted) RS = receiving slitThe data was obtained and analyzed using DMSNT v. 1.37 softwareavailable from Scintag, Inc. The x-ray diffraction pattern obtained isshown in FIG. 1.

Example 10 Preparation of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino)methyl)-2-furyl]-4-quinazolinamineditosylate monohydrate (monohydrate form of compound of formula II)

A 20 L reactor was charged with 1 wt (930 g, 1.0 mol) ofN-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate anhydrate prepared using the procedure of Example 8. To thiswas added 10 volumes of a pre-mixed 8:2 THF:deionized water solution andthe reactor was heated to 65° C. Complete dissolution was observed at50° C. The clear reaction mixture was transferred to another 20 Lreactor through a stainless steel jacketed transfer hose that wasequipped with an in-line 5.0 μm cartridge filter. The empty 20 L reactorand the filter line were washed with 0.2 vol of the pre-mixed 8:2THF:deionized water solution. An additional 1 vol of pre-mixed 8:2THF:deionized water solution was used to wash the material into thereaction mixture. The 20 L reactor was heated to ˜80° C. The reactiontemperature was then ramped down to 55° C. over 2 hours and then to 45°C. over 10 hours. After 10 hours, the temperature was adjusted to 25° C.and the reaction mixture allowed to stir at room temperature for 45minutes. The yellow precipitate was drained from the bottom of the 20 Lreactor into a ceramic filter lined with paper. The flow was fast andsmooth and the filter rate very good. The yellow filter cake was washedwith 0.6 volumes of a pre-mixed 8:2 THF:deionized water solution and theyellow solid was air dried for 4 hours and placed into a glass tray. Theglass tray was placed in a vacuum oven under house vacuum (˜18 in Hg) at60° C. with a nitrogen bleed for 2 days. After removal from the oven,the material was sampled accordingly. The yield was 743 grams (0.8 wt,80%; 930 g th) as a bright yellow, crystalline solid.

Approximately 50 mg of the product was transferred to a Karl FisherVolumetric Moisture Apparatus (model DL35, Mettler, Hightstown, N.J.),which was operated according to the manufacturer's instructions. Themonohydrate water content was determined to be 1.99%, which is inagreement with the theoretical value of 1.92%.

Example 11 X-Ray Diffraction of Monohydrate Ditosylate Salt

A monohydrate ditosylate salt sample prepared according to Example 10was dusted on to a silicon zero background plate of a Scintag XDS2000Diffractometer. The powder x-ray diffraction pattern of the sample wasobtained under the following conditions. Geometry: θ/θ Asset: 0038018Seifert High Voltage ID3000 generator, S/N 90 67 1422 X-ray tube tower:Seifert type V4, 60 kV max, 40 mA max, X-ray diffraction tube: AEGFK-60-10 copper anode tube, 60 kV max, 2 kW max, normal focus (1 × 10mm) Scintag Peltier cooled Si(Li) Solid 250 mm State Detector Model B3AGoniometer radius: Operating Conditions: X-ray tube voltage: 45 kV X-raytube current: 40 mA Scan Conditions: chopper: 0.02 deg continuous scanmode 0.25 deg 2θ/min scan rate: sample spinner: ON (1 rotation/sec) DS =1 mm; SS(i) = 2 mm SS(d) = 0.5 mm; RS = 0.3 mm DS = divergent slit(incident beam) SS(i) = scatter slit (incident) SS(d) = scatter slit(diffracted) RS = receiving slitThe data was obtained and analyzed using DMSNT v. 1.37 softwareavailable from Scintag, Inc., The x-ray diffraction pattern obtained isshown in FIG. 2.

Example 12 Preparation of(4-(3-Fluoro-benzyloxy)-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)quinazolin-4-yl)-amineditosylate. (compound of formula IV)

The HCl salt of5-(4-[3-bromo-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde(prepared according to Procedure C, page 56 of WO 99/35146) wasconverted to the tosylate salt according to the procedure of Example 7.The resultant furan 2-carbaldehyde tosylate product was used to preparethe(4-(3-Fluoro-benzyloxy)-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)quinazolin-4-yl)-amineditosylate according to the procedure of Example 8.

Example 13 Preparation of(4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)quinazolin-4-yl)-amineditosylate (compound of formula III)

The HCL salt of(4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)quinazolin-4-yl)-aminewas prepared according to Procedure F. pages 57-59 of WO 99/35146 andthen converted to the(4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)quinazolin-4-yl)-amineditosylate salt according to the procedures of Example 7.

Example 14 Conversion of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate-monohydrate to anhydrate

Approximately 50 mg of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate monohydrate prepared according to the procedure of Example 10was weighed into a 1-dram vial to which 1-mL of MeOH or 2-methoxyethanolwas added. The slurry was stirred in a 25° C. water bath for 4 days,after which the solid was separated by filtration and dried under housevacuum at 40° C. for 1 day. The x-ray diffraction pattern of the driedsolid from both MeOH and 2-methoxyethanol matched that ofN-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate anhydrate.

Example 15 Conversion of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino)methyl)-2-furyl]-4-quinazolinamineditosylate-anhydrate to monohydrate

To a 1 L 3-necked round bottomed flask equipped with an overhead stirrerwas placed 77.0 g (0.08 mol) N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate anhydrate prepared according to the procedure of Example 12.To the yellow solid was added deionized water (10 vols) and the slurrywas left to stir at RT. At one hour time points, small aliquots wereremoved, filtered through paper on a Buchner funnel and dried in avacuum oven at 60° C. for 12 hrs. Each sample was submitted for XRDanalysis [t=45 min, anhydrate; t=2.5 hrs, anhydrate; t=3.5 hrs, mixtureof anhydrate/monohydrate; t=>12 hrs, monohydrate.] The reaction slurrywas left to stand at room temperature for 36 hrs. The bright yellowmaterial was then filtered through paper on a Buchner funnel and airdried overnight. The material was placed in a vacuum drying oven at 55°C. with a nitrogen bleed for 96 hrs. The isolated yield was 74 grams(96% Th). A sample was submitted for XRD which indicated it wasN-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]aminomethyl)-2-furyl]-4-quinazolinamineditosylate monohydrate.

Example 16 Moisture sorption testing N-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate monohydrate salt

Approximately 12 mg of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate monohydrate salt prepared according to Example 10 was weighedinto a sample pan of a moisture sorption apparatus (model numberSGA-100, made by VTI). The sample was dried at 60° C. under a nitrogenstream until the weight loss was less than 0.015% in 5 minutes. Therelative humidity (RH) was then increased (adsorption) to 5, 15, 25, 35,45, 55, 65, 75, 85 and 95%—at each step, equilibrium was defined as aweight change of less than 0.015% in 5 minutes. The relative humiditywas then decreased (desorption) to 90, 80, 70, 60, 50, 40, 30, and 20%with the same equilibrium condition. The sorption curve (y-axis:Weight—% change vs. x-axis: % RH) is depicted in FIG. 3(a).

Example 17 Moisture sorption testing N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino)methyl)-2-furyl]-4-quinazolinaminedi-HCl salt

Approximately 15 mg of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinaminedi-HCl salt

was weighed into a sample pan of a moisture sorption apparatus (modelnumber SGA-100, made by VTI). The sample was dried at 60° C. under anitrogen stream until the weight loss was less than 0.015% in 5 minutes.The relative humidity was then increased (adsorption) to 5, 15, 25, 35,45, 55, 65, 75, 85 and 95%—at each step, equilibrium was defined as aweight change of less than 0.015% in 5 minutes. The relative humiditywas then decreased (desorption) to 90, 80, 70, 60, 50, 40, 30, and 20%with the same equilibrium condition. The sorption curve (y-axis:Weight—% change vs. x-axis: % RH) is depicted in FIG. 3(b).

Example 18 Relative physical stability ofN-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl)-6-[5-(([2-(methanesulphonyl)ethyl]amino)methyl)-2-furyl]-4-quinazolinamineditosylate anhydrate and monohydrate crystal forms

A slurry equilibration method was used to determine the relativephysical stability of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamineditosylate anhydrate and monohydrate crystal forms. The method involvedpreparation of organic/aqueous slurries of known water activitycontaining mixtures of the anhydrate and monohydrate forms. The slurriesequilibrated to the lowest free energy form, from which the relativephysical stability was determined as a function of relative humidity.

Methanol (MeOH)/H₂O mixtures were prepared by volume and composition wasconverted to mole fraction (X_(w)) using molecular weights and roomtemperature densities (0.787 g/mL for MeOH and 1.00 g/mL for H₂O). Wateractivity (a_(w)) was calculated from:a _(w)=0.0056+1.398X_(w)−0.647X _(w) ²+0.153X _(w) ³+0.0845X _(w) ⁴(Zhu, H., Yuen, C., Grant, D. J. W., 1996. Influence of water activityin organic solvent+water mixtures on the nature of the crystallizingdrug phase. 1. Theophylline. Int. J. Pharm. 135, 151-160.)

A 1:1 ratio of both crystal forms was added to vials and reconstitutedwith the MeOH/H₂O mixtures. After initial mixing, an aliquot was removedand dispensed for analysis by powder X-ray diffraction (model PADV,Scintag, Cupertino, Calif.) to ensure that peaks of both crystal formswere detectable. Samples were stirred and equilibrated at 25° C. in awater bath.

The results in Table III illustrate the crystal form conversion patternas a function of calculated water activity/RH. The transformation ratewas very rapid, as observed by powder X-ray diffraction (pXRD), notchanging from the 1 day timepoint onward. The pXRD patterns are providedin FIG. 5. The top panel shows the results for the pure crystal forms ofthe anhydrate and monohydrate. The middle panel illustrates that the 1:1mixture converted to the anhydrate in the liquid phase with a wateractivity equivalent to 7% RH. Likewise, the bottom panel demonstratesthat the monohydrate is the stable form at a water activity equivalentto 15% RH. The summary in Table III notes that in general, themonohydrate becomes the thermodynamically stable form somewhere between7-15% RH and remains stable up through 100% RH. TABLE III Water WaterVolume Mole (%) Fraction RH (%) Equilibrium Form 0 0.00 0 Anhydrate 20.04 7 Anhydrate 5 0.11 15 Monohydrate 10 0.20 26 Monohydrate 20 0.36 43Monohydrate 40 0.60 66 Monohydrate 60 0.77 80 Monohydrate 80 0.90 91Monohydrate 90 0.95 95 Monohydrate 100 1.00 100 MonohydrateBiological Data

Compounds of the present invention were tested for erbB family proteintyrosine kinase inhibitory activity in substrate phosphorylation assaysand cell proliferation assays.

Substrate Phosphorylation Assay

The substrate phosphorylation assays use baculovirus expressed,recombinant constructs of the intracellular domains of c-erbB-2 andc-erbB-4 that are constitutively active and EGFr isolated fromsolubilised A431 cell membranes. The method measures the ability of theisolated enzymes to catalyse the transfer of the g-phosphate from ATPonto tyrosine residues in a biotinylated synthetic peptide(Biotin-GluGluGluGluTyrPheGluLeuVal). Substrate phosphorylation wasdetected following either of the following two procedures:

a.) c-ErbB-2, c-ErbB4 or EGFr were incubated for 30 minutes, at roomtemperature, with 10 mM MnCl₂, 10 mM ATP, 5 mM peptide, and testcompound (diluted from a 5 mM stock in DMSO, final DMSO concentration is2%) in 40 mM HEPES buffer, pH 7.4. The reaction was stopped by theaddition of EDTA (final concentration 0.15 mM) and a sample wastransferred to a streptavidin-coated 96-well plate. The plate was washedand the level of phosphotyrosine on the peptide was determined using aEuropium-labelled antiphosphotyrosine antibody and quantified with atime-resolved fluorescence technique.

b.) ErbB2 was incubated for 50 minutes at room temperature with 15 mMMnCl₂, 2 mM ATP, 0.25 mCi [g-³³P] ATP/well, 5 mM peptide substrate, andtest compound (diluted from a 10 mM stock in DMSO, final DMSOconcentration is 2%) in 50 mM MOPS pH 7.2. The reaction was terminatedby the addition of 200 ml of PBS containing 2.5 mg/mlstreptavidin-coated SPA beads (Amersham Inc.), 50 mM ATP, 10 mM EDTA and0.1% TX-100. The microtitre plates were sealed and SPA beads wereallowed to settle for at least six hours. The SPA signal was measuredusing a Packard Topcount 96-well plate scintillation counter (PackardInstrument Co., Meriden, Conn.).

The compounds tested were the products of Examples 8, 12, and 13, inbuffered solution as indicated. Representative results are shown inTable IV for EGFR, erbB2, and erbB4 tyrosine kinase inhibition. Also,structures for the free base of the salts of Examples 8, 12, and 13 aregiven. TABLE IV Example # Structure EGFR ErbB2 ErbB4  8

+++ +++ ++ 12

+++ +++ ++ 13

+++ +++ + IC₅₀ values Symbol <0.10 uM +++ 0.10-1.0 uM ++ 1.0-10.0uM + >10.0 uM - Not determined NDCellular Assays: Methylene Blue Growth Inhibition Assay

Human breast (BT474), head and neck (HN5) and gastric tumor (N87) celllines and human foreskin Fibroblasts (HFF) were cultured in low glucoseDMEM (Life Technologies 12320-032) containing 10% fetal bovine serum(FBS) at 37° C. in a humidified 10% CO₂, 90% air incubator. The SV40transformed human mammary epithelial cell line HB4a was transfected witheither human H-ras cDNA (HB4a r4.2) or the human c-erbB2 cDNA (HB4ac5.2). The HB4a clones were cultured in RPMI containing 10% FBS, insulin(5 μg/ml), hydrocortisone (5 μg/ml), supplemented with the selectionagent hygromycin B (50 μg/ml). Cells were harvested using trypsin/EDTA,counted using a haemocytometer, and plated in 100 ml of the appropriatemedia, at the following densities, in a 96-well tissue culture plate(Falcon 3075): BT474 10,000 cells/well, HN5 3,000 cells/well, N87 10,000cells/well, HB4a c5.2 3,000 cells/well, HB4a r4.2 3,000 cells/well, HFF2500 cells/well. The next day, compounds were diluted in DMEM containing100 mg/ml gentamicin, at twice the final required concentration, from 10mM stock solutions in DMSO. 100 ml/well of these dilutions were added tothe 100 ml of media currently on the cell plates. Medium containing 0.6%DMSO was added to control wells. Compounds diluted in DMEM were added toall cell lines, including the HB4a r4.2 and HB4a c5.2 cell lines. Thefinal concentration of DMSO in all wells was 0.3%. Cells were incubatedat 37° C., 10% CO₂ for 3 days. Medium was removed by aspiration. Cellbiomass was estimated by staining cells with 100 μl per well methyleneblue (Sigma M9140, 0.5% in 50:50 ethanol:water), and incubation at roomtemperature for at least 30 minutes. Stain was removed, and the platesrinsed under a gentle stream of water, and air-dried. To release stainfrom the cells 100 μl of solubilization solution was added (1% N-lauroylsarcosine, Sodium salt, Sigma L5125, in PBS), and plates were shakengently for about 30 minutes. Optical density at 620 nM was measured on amicroplate reader. Percent inhibition of cell growth was calculatedrelative to vehicle treated control wells. Concentration of compoundthat inhibits 50% of cell growth (IC₅₀) was interpolated using nonlinearregression (Levenberg-Marquardt) and the equation,y=V_(max)*(1−(x/(K+x)))+Y2, where “K” was equal to the IC₅₀.

Table V illustrates the inhibitory activity of compounds of the presentinvention as IC₅₀ values in μM against a range of tumor cell lines.Using HFF as a representative human normal cell line, values forcytotoxicity are supplied as IC₅₀ values in micromolar. A measure ofselectivity between normal and tumor lines is provided as well. TABLE VN87 BT474 IC₅₀ IC₅₀ HN5 uM uM IC₅₀ uM Example # Cell Cell Cell  8 ++++++ +++ 12 +++ +++ +++ 13 +++ +++ +++ IC₅₀ value Symbol <5 μM +++ 5-25μM ++ 25-50 μM + >50 μM − Not determined ND

1. (canceled)
 2. A process for preparing a compound of formula (C),

comprising the steps of: reacting a compound of formula (A)

with a compound of formula (B)

to form the compound of formula (C), wherein U is an organic group; andthe compound of formula (A) is generated in situ; and L is iodine orbromine; R is —C(Q)(T)W where Q and T are independently selected from—OCH₃ or —OCH₂CH₃ and W is hydrogen; and Z is B(OH)₂; or the compound offormula (A) is generated in situ; and L is iodine or bromine; R is—C(O)H; and Z is B(OH)₂; or the compound of formula (B) is generated insitu, and L is B(OH)₂; R is —C(O)H; and Z is bromine.
 3. A process asclaimed in claim 2 wherein U represents a phenyl or 1H-indazolyl groupsubstituted by an R² group and optionally substituted by at least oneindependently selected R⁴ group; wherein R² is selected from a groupcomprising benzyl, halo-, dihalo- and trihalobenzyl, benzoyl,pyridylmethyl, pyridylmethoxy, phenoxy, benzyloxy, halo-, dihalo- andtrihalobenzyloxy and benzenesulphonyl; and each R⁴ is selected from thegroup hydroxy, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C,-4alkoxy, amino, C₁₋₄ alkylamino, di[C₁₋₄ alkyl]amino, C₁₋₄ alkylthio,C₁₋₄ alkylsulphinyl, C₁₋₄ alkylsulphonyl, C₁₋₄ alkylcarbonyl, carboxy,carbamoyl, C₁₋₄ alkoxycarbonyl, C₁₋₄ alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-di(C₁₋₄ alkyl)carbamoyl, cyano, nitro andtrifluoromethyl.
 4. A process as claimed in claim 3 wherein R²represents 3-fluorobenzyloxy.
 5. A process as claimed in claim 3 whereinthe phenyl or 1H-indazolyl group of U is substituted by an R⁴ group,wherein R⁴ represents halo.
 6. A process as claimed in claim 1 wherein Uis selected from the group consisting of3-fluorobenzyloxy-3-chlorophenyl, benzyloxy-3-chlorophenyl,benzyloxy-3-trifluoromethylphenyl, (benzyloxy)-3-fluorophenyl,(3-fluorobenzyloxy)-3-fluorophenyl or (3-fluorobenzyl)indazolyl.
 7. Aprocess as claimed in any claim 1 wherein the compound of formula (A) isgenerated in situ; L is iodine or bromine; and Z is B(OH)₂.
 8. A processas claimed in any claim 1 wherein the compound of formula (A) isgenerated in situ; L is iodine; and Z is B(OH)₂.
 9. A process as claimedin claim 1 wherein the compound of formula (C) is5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde.